The EMBO Journal Vol. 19,pp. 78-83, 2000, Copyright © European Molecular Biology Organization

Anchoring proteins confer G protein sensitivity to an inward-rectifier K⁺ channel through the GK domain

Hiroshi Hibino, Atsushi Inanobe, Masayuki Tanemoto, Akikazu Fujita, Katsumi Doi, Takeshi Kubo, Yutaka Hata, Yoshimi Takai² and Yoshihisa Kurachi

Departments of Pharmacology II, ¹ Otolaryngology and ³ Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2, Yamada-oka, Suita, Osaka 565-0871 and ² Takai Biotimer Project, ERATO, Japan Science and Technology Corporation, c/o JCR Pharmaceuticals Co. Ltd, 2-2-10 Murotani, Nishi-ku Kobe 651-2241, Japan
⁴   Corresponding author
   e-mail: ykurachi{at}pharma2.med.osaka-u.ac.jp

Anchoring proteins cluster receptors and ion channels at postsynaptic membranes in the brain. They also act as scaffolds for intracellular signaling molecules including synGAP and NO synthase. Here we report a new function for intracellular anchoring proteins: the regulation of synaptic ion channel function. A neuronal G protein-gated inwardly rectifying K⁺ channel, Kir3.2c, can not be activated either by M₂-muscarinic receptor stimulation or by G overexpression. When coexpressed with SAP97, a member of the PSD/SAP anchoring protein family, the channel became sensitive to G protein stimulation. Although the C-terminus of Kir3.2c bound to the second PDZ domain of SAP97, functional analyses revealed that the guanylate kinase (GK) domain of SAP97 is crucial for sensitization of the Kir3.2c channel to G protein stimulation. Furthermore, SAPAP1/GKAP, which binds specifically to the GK domain of membrane-associated guanylate kinases, prevented the SAP97-induced sensitization. The function of a synaptic ion channel can therefore be controlled by a network of various intracellular proteins.